Micro Gets Macro

The bits of repetitious DNA called microsatellites are getting bigger as we evolve--which may increase the incidence of genetic disease.

Humans have less hair than our ape and monkey cousins, and we walk on two feet. By and large we are also more intelligent and creative. Now researchers in England have discovered another distinguishing feature: humans have longer microsatellites. That leaves us more prone to certain genetic diseases.

Microsatellites are strings of repetitious DNA, with each string consisting of a sequence of two to five nucleotides repeated many times. Gene mappers use microsatellites as readily distinguishable landmarks, but they’re of no known use to the rest of us. Most occur between genes in neutral regions of DNA--that is, in regions that do not code for proteins.

Some microsatellites do occur within genes, however, and some of those are harmful. At least seven diseases, including Huntington’s disease and fragile X syndrome, a form of mental retardation, have now been linked to trinucleotide repeats--microsatellites in which the repeated sequence consists of three nucleotides. In Huntington’s, for instance, the nucleotide sequence cytosine-adenine-guanine, or CAG, repeated many times in a certain gene results in a faulty protein that apparently causes the degeneration of the nervous system.

But trinucleotide repeats seem to do their damage only when they have reached a certain threshold length--around 36 CAG repeats in the case of Huntington’s. We all carry the microsatellites, but in most of us the number of repeats is well below the disease threshold. Frighteningly, though, microsatellites can cross the threshold from one generation to the next. This means that healthy parents can have a child with, say, Huntington’s or fragile X syndrome.

Now it seems that microsatellites grow longer on another time scale as well--evolutionary time. Geneticist David Rubinsztein of Addenbrooke’s Hospital in Cambridge noticed that humans carry many more repeats of the Huntington’s CAG sequence than do chimps. So he decided to compare the length of human microsatellites with those of other primates. He and his colleagues measured the lengths of 42 microsatellites in humans, chimps, gorillas, orangutans, baboons, and macaques.

The researchers found that human microsatellites are longer on average than those of other primates. In the millions of years since we diverged from our kin, our microsatellites have apparently grown at a faster rate than theirs.

Why? Natural selection isn’t likely to be the reason; long microsatellites convey no known advantage, and it’s hard to imagine an advantage to having all our microsatellites grow longer, as opposed to a particular one. The alternative, says Rubinsztein, is that mutations simply occur at a faster rate in humans. One way that could happen is if humans have a mutant form of DNA polymerase, the enzyme responsible for copying DNA when cells divide--a mutant that promotes further genetic mutations. The enzyme might sometimes allow the DNA to slip during copying, resulting in the insertion of extra nucleotides.

Rubinsztein, however, favors a different explanation: he thinks the human mutation rate may be higher because men reproduce at a later age than do other male primates. Because men make sperm throughout their lives, whereas virtually all of a woman’s ova are formed while she’s still in the womb, he explains, the older the man, the greater the number of cell divisions that have occurred in the making of his sperm. And since mutations tend to happen during cell division, older men have a greater risk of passing on a mutation that lengthens a microsatellite--such as a disease-causing trinucleotide repeat.

Trinucleotide repeat diseases have never been seen in any other species studied by geneticists. If microsatellites have generally expanded faster in humans, then those trinucleotide repeats would probably have done the same, says Rubinsztein, and they’re more likely to reach that critical disease-causing length much sooner in humans. That could explain why we see these diseases only in humans. It also leads to an unsettling prediction: over thousands of years, as all our microsatellites get longer, the incidence of these diseases is likely to rise.